DESCRIPTION (Adapted from applicants abstract): The long term objective of this research is to identify the mechanism(s) involved in the etiology of depression and its relief by antidepressants. Antidepressants can be broadly classified into three types: Those that inhibit monoamine oxidase, those that block re-uptake of monoamines and those that specifically block re-uptake of serotonin. The fact that these antidepressants work on different mechanisms suggests that the biochemical cascades they initiate ultimately converge on a common process. Is altered neuronal circuitry, indicated by significant and selective changes in dendritic spine density, a part of that common process? The specific aim of this proposal is to use a novel method for estimating dendritic spine density to test the hypothesis that chronic exposure to the 3 different types of antidepressants causes specific circuits in the brain to become rewired. Histochemistry for two novel markers for dendritic spines (spinophilin and phallodin) will be used in conjunction with confocal laser microscopy, a novel modification of the "dissector" technique, and a novel computerized imaging and quantification system. The proposed studies should: 1) demonstrate that the new method has merit; and 2) directly test the hypothesis that antidepressants cause significant changes in brain wiring as evidenced by altered dendritic spine densities. The new technique should be broadly applicable to other studies on brain plasticity. A finding that antidepressants cause specific parts of the brain to be rewired would identify a new mechanism by which antidepressants may work and serve as a building block on which many new studies investigating depression and its treatment could be based.